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Citation: European Journal of Cancer Supplements, Vol 7 No 2, September 2009, Page 341
A.F. Sobrero1, A. Pessino1, V. Andretta1, E. Bennicelli1, G. Fornarini1, F. Caprioni1, D. Comandini1, L. Orsino1, A. Lambiase2, C. Bordignon2
1San Martino Hospital, Department of Oncology, Genoa, Italy
2MolMed, Clinical Development, Milan, Italy
Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds an aminopeptidase N expressed on tumor vessels. In preclinical models, NGR-hTNF showed synergism with chemotherapy even at low doses. Two phase I trials previously selected 0.8 μg/m2 and 45 μg/m2 as optimal-biological and maximum-tolerated dose, respectively.
Methods: Two sequential cohorts of 12 CRC patients (pts) failing standard therapies were planned to receive 2 doses of NGR-hTNF given at 0.8 μg/m2 (LD) or 45 μg/m2 (HD) as 1-hour intravenous infusion every 3 weeks (q3w). XELOX consisted of oxaliplatin 100 mg/m2 plus capecitabine 825 mg/m2 twice-daily for 14 days q3w. Primary study objective was safety (≤2/12 pts with grade 3–4 toxicity related to NGR-hTNF). Secondary aims included tolerability and clinical activity. Tumor restaging was done q6w.
Results: From January 2008 to March 2009, 12 pts (median age, 57 years, range 40–74; M/F 7/5; PS 0/1 11/1) were enrolled in the LD cohort and 11 pts (median age, 54 years, range 43–65; M/F 7/4; PS 0/1 8/3) in the HD cohort. All pts had previously received oxaliplatin and fluoropyrimidines. The median number of prior regimens was 3 (range, 1–4) in LD and 2 (range, 2–4) in HD. Globally, 44 cycles (median, 3; range, 2–6) and 24+ cycles (median, 2; range, 1–4+) were delivered in LD and HD, respectively. The combination was well tolerated. No grade 3–4 study drug-related toxicities were observed in both cohorts, most common grade 1–2 toxicity being short-lived, infusion-time related chills (58% in LD and 54% in HD). In the LD cohort, 1 partial response, 5 stable diseases (SD) lasting for a median time of 5.0 months (range, 3.0–8.6), and 6 progressions (PD) were observed. Maximal change in target lesions of SD pts ranged from 0% growth to 46% shrinkage. The median PFS was 3.4 months (range, 1.5–9.4), whereas the median ratio between PFS on current study and on prior therapy was 0.92. In the HD cohort, there are currently 3 SD, 6 PD, and 2 too-early, as best response.
Conclusions: Both NGR-hTNF doses were safely administered in combination with XELOX in heavily pretreated CRC pts, without worsening of chemo-associated toxicity.
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